The Immune Laminitis Connection

By Joseph Thomas, PhD

Printed in: Natural Horse
Volume 9, Issue 1

Laminitis is considered a relentless disease because once a horse has had one episode the chance of having another is escalated. There are two primary reasons for this. One is that laminitic horses have a metabolic disease with the same glucose and insulin profile of type 2 diabetes, i.e. elevated blood glucose levels with deficient insulin and/or abnormal insulin action.₁ The other reason is that horses with laminitis have immune system deficiencies that make recovery difficult and leave them vulnerable to infection, such as chronic hoof abscesses.

Having both an impaired immune system and elevated glucose levels leads to easily acquired infections as well as a heightened sensitivity to vaccinations. When there is even the slightest challenge or infection present, the already elevated glucose concentrations in the liver and the circulating blood increase, which increases the risk of laminae separation. In this article we look at the immune system and how it functions in a healthy horse and in a laminitic horse.

What does the immune system do, and how does it work?

The function of the immune system is to protect the horse from foreign organisms and substances. This complex system of cells and molecules has evolved, over millions of years, into both an innate immune system and an adaptive immune system. Together they work to rapidly and efficiently remove virulent antigens from the horse’s body through the activity of white blood cells (leukocytes).

The innate immune system has developed a range of encoded responses to a large group of antigens. Basically, antigens are anything that the body detects as harmful (such as toxins or viruses) and to which it immediately activates an immune response. The primary leukocytes of the innate immune system relevant to this discussion are neutrophils, monocytes and eosinophils. While each of these has specific functions within the immune system, they work interdependently to protect the horse’s body.

Once antigens are detected, these leukocytes of the innate immune system will either ‘ingest’ and destroy them or activate a series of actions to slow down their effects. If the innate immune system is not completely effective in this initial defensive action, it then ‘calls-upon’ the adaptive immune system, which has more potent and ‘highly developed’ cells, to engage the antigens.

The key feature of the adaptive immune system is that it develops specific responses to new antigens so that on subsequent exposures it has an immunologic memory to draw on, resulting in a more rapid and forceful immune response. The leukocytes that respond through this system are lymphocytes and they are the body’s primary defense against bacterial and viral infections.₂

What goes on in the laminitic horse's immune system?

To quickly review, a laminitic or metabolic syndrome horse ingests fructans (complex sugar) that are unable to be assimilated in the small intestine and swiftly make their way on to the colon where the fructans quickly ferment, significantly altering the intestine’s bacterial population and creating a highly acidic intestinal environment. The result is damage to the intestinal lining, releasing toxins into the circulating blood. When these toxins in the blood reach the hoof, dilated blood vessels allow them rapid and clear entry into the hoof capsule. The toxins, now inhabiting the inner hoof, trigger a floodgate release of MMPs (matrix metalloproteinases) resulting in laminae separation.₃

* A dysfunctional inflammatory process sets in

The separation of the laminae is an injury that immediately activates the innate immune system’s inflammatory response. This healthy, natural response serves to ‘wall-off’ both the injurious toxic agent (antigen) and the injured laminae tissue. But in laminitic horses, the initial inflammatory response to the beginning of the laminae separation is not strong enough to encapsulate the injury. The eosinophils, that work to dampen inflammation, are deplete in these horses and so are unable to contain or limit the inflammation. So it ‘spills’ over into a pathological local inflammation creating heat and causing fluid buildup within the confined space of the inner hoof.

This is the beginning of pain for the horse during an acute episode. The macrophages recruit the lymphocytes, but there is another problem; laminitic horses also have low levels of mature lymphocytes. Although, they are called to the task of seek, destroy, and cleanup, they are not up to completing it. This makes the injury slow to heal and leaves the horse’s hoof with a remaining bacterial field vulnerable to repeat infections. This is the source of chronic hoof abscesses associated with laminitic and metabolic syndrome horses.

“the strength and healing environment in laminitic hooves are different from those of normal hooves......laminitis obviously greatly degrades the laminar attachment causing them to separate much more easily than normal.” Dr. Christopher Pollitt, 2004

* 11beta-Hydroxysteroid Dehydrogenase1 (11beta-HSD1) works against the immune system

The second article in this laminitis series, “The Missing Link in Laminitis” explained a pivotal process in laminitis concerning the expression of the enzyme 11beta-HSD1 and sustained activation of glucocorticoids (conversion of inactive cortisone to active cortisol) at tissue-specific target sites. A significant effect of this crucial process is the production of excess glucose in the liver and the circulating blood, which is a fundamental similarity between laminitis and type 2 diabetes.₄

This same pivotal-switch, 11beta-HSD1, contributes to the effectiveness of the innate and adaptive immune systems in a healthy horse. Yet in a laminitic horse, in which there is over expression of the enzyme, 11beta-HSD1 inhibits monocyte-macrophage differentiation, a process essential to immediate immune responsiveness.₅₃ Also, 11beta-HSD1’s expression within lymphocytes produces a substantial concentration of immature cells, and that lowers the number of effective lymphocytes available to fight bacterial and viral infections.₆ So this enzyme’s activity inhibits the effectiveness of both the innate and adaptive immune systems.

• the presence of microorganisms and/or toxins in the blood cause increased adrenal secretion, and elevated cortisol. This contributes to increased glucose levels in the liver and bloodstream as well as interfering with insulin’s function of impelling this much-needed glucose into cells for life nourishment.
• glucocorticoids produce a depletion of eosinophils which contain anti-inflammatory enzymes that down regulate or terminate ongoing inflammatory processes. Low levels of eosinophils also increase adrenal cortex steroid secretion.
• glucocorticoids cause a redistribution of T lymphocyte cells (essential mediators of all cellular immunity) from blood circulation into other ‘compartments’ thereby down-regulating all cellular immunity, primarily by producing a concentration of immature lymphocytes.

Further substantiation of this data is evidenced in my findings through extensive collection of blood work profiles of laminitic horses. These findings indicate that most laminitic horses have a deficiency of eosinophils and lymphocytes and a high concentration of neutrophil bands, which are immature neutrophils.

Hoof abscesses become common place

Abscesses are notoriously frequent in laminitic horses and seem to never go away. Given the inadequate immune response of horses with metabolic syndrome, this makes sense.

There are two important underlying components to abscess formation. The first of these is the inability of the innate immune system to remove fluid build-up and microorganisms as well as trapped cell fragments. The second is the growth of bacteria that both the innate and adaptive immune systems are unable to eliminate.

Following a laminitic episode, there is dead tissue, microorganisms, fluid swelling, and inflammation remaining in the hoof. Until the immune process can completely remove these, the hoof remains vulnerable to abscesses.

Abscesses, in these horses, can get so severe that the horse will have extreme difficulty in movement. This can happen without any visual indications at the sole level. The ‘out-of-control’ inflammatory response trying to take care of the growing abscess will create heat at the coronary band area along with debilitating pain from extreme inflammation in the confined hoof capsule. These signs are often mistaken for an imminent or yet another laminitic episode when they are actually indications of abscesses.

Evidence of a link to immunologic hyperactivity in chronic laminitis

Researchers from Texas A&M University have conducted a well-designed study that implicates a link between routine vaccination and acute episodes of horses with chronic laminitis. Their results were quite convincing, presenting clear evidence that there is a relationship between vaccines and acute episodes brought about through changes in the immune system produced by the chronic laminitis, which then leads to a heightened sensitivity to vaccines.

The Texas A&M researchers injected chronically laminitic and healthy horses with a variety of antigens and reported immunologic ‘reactions’ at defined intervals of time. The results clearly showed that chronically laminitic horses have a much stronger peak reaction than healthy horses, characterized by an infiltration of immature neutrophils along with local inflammation, fluid buildup and vascular damage.₇ The information presented in the present article gives an explanation for their results.

Conclusion – What does this all mean for your horse?

The pervasive idea that the inflammation of the laminae causes the separation during an acute episode of laminitis is explicitly disputed in this article. Rather than the inflammation being the origin of the separation, it is a secondary consequence of the inefficient responses of the innate and adaptive immune systems of laminitic horses. Laminitis, itis (inflammation) of the laminae, indeed occurs but it is the end result of a runaway cascade of events (defects in the essential leukocyte constituents following the initiation of laminae separation set off by the floodgate release of MMPs).

Understanding the participation of the immune system within the underlying mechanisms of the metabolic syndrome in horses is an important step to implementing a cure. As long as the idea persists that laminae separation initially occurs due to inflammation, the treatment strategies will follow course keeping this disease focused on the hoof. This means that each acute episode will be treated as a discreet event and the metabolic dysfunction from which they stem will not be addressed.

Treatment of the diabetic aspect of this disease is the only recovery course for these horses, especially considering that the immune system of these horses is not just inadequate but also a coordinated partner in the continuation of the underlying disease. As long as their immune system remains ineffective these horses’ glucose will remain elevated and rise, along with the risk of an acute episode, when a demand for defensive action is placed on it.

What about movement?

Laminitic horses do have all the health and immunity issues mentioned in this article and that creates a serious problem regarding the question: what needs to be done about their movement? It is often recommended that horses with a predisposition towards a metabolic disease (as evidenced by their ample weight and fat deposits, aka Easy Keeper) or horses that have had a prior laminitic episode lose weight and get on an exercise program - but this must be carefully considered for each individual horse.

It is important to understand that these horses are all living with some degree of metabolic dysfunction and that weight loss, in and of itself, is just a small piece of the much larger puzzle. Each of these horses has a different glucose/insulin ratio, triglyceride level, lymphocyte and red blood cell concentration, and a different immune system function. So each horse is uniquely sick and will respond differently to an identical laminitic trigger and to a particular exercise regimen.

The farther along a horse ‘lives’ on the metabolic continuum of these physiological characteristics, i.e. the ‘sicker’ the horse is and the more at risk of an acute laminae separation episode, the more likely an ‘intense’ exercise program or even long rides will make the entire disease process worse.

This cannot be stressed enough. Given the deficiency in the innate and adaptive immune systems in the laminitic horse, the individual horse’s movement ‘threshold’ has a very real limit that if exceeded, places this horse in danger. The risk is one of sustained infections, relentless abscesses, pain, increases in already existing elevated glucose, depression, fatigue and an overall vulnerability to recurring acute laminitic episodes.

As caretakers, we need to continually assess their condition by careful observation, or if need be, by appropriate laboratory blood work analysis, so that we do not push them past their immune limits and exacerbate their metabolic disease, leaving them to suffer the consequences of these actions.

Laminitic horses, like all horses, need movement, but they need free choice movement, when they can move, and they need to be able to determine when, what type of movement and for how long, within reasonable constraints. When horses have the freedom to choose their movement it is quite likely that they will choose within their limits. Separating some of the things they will walk for - such as water, hay and salt - can encourage movement. There are situations where this freedom may not always be possible to give; yet we must do the best we can.

Your horse can recover

This is the third and final article in my laminitis series and I hope that despite the seriousness of the systemic problems described, you will find this information both helpful and hopeful. These articles were written to pass on the results of my research in the hope that it will help you understand what is really going on in your laminitic horse. The drive behind the research has been my need to know the pathophysiological roots of this disease so that I could more precisely and effectively formulate Chinese herbal solutions to help all our horses recover.

The needs of immune deficient horses can be met with sophisticated herbal formulations. Red blood cells, white blood cells and their specific constituents of lymphocytes, macrophages and neutrophils can be elevated by specific combinations of herbs, assisting the horse’s body to produce mature leukocytes and maintain their continual production of these essential immune elements.

This is exactly the approach that is needed for an effective treatment for horses with this metabolic disease. When used with an herbal combination that treats the underlying metabolic disease, recovery is accelerated as evidenced by the vast number of horses that are using our Laminitis Intervention Program and living a healthier life with much more freedom. Your horse can recover and live a healthy life too.

 

Glossary of terms and definitions:

antigen:

any substance, such as toxins or foreign particles, bacteria and tissue cells, capable of inducing an immune response.

inflammatory response:

a natural, initial protective response of the innate immune system elicited by an injury or destruction of tissue. This response serves to localize the injurious agent and the injured tissue. Leukocytes can then digest and remove the antigen and dead tissue. The inflammation is an early defensive measure by the innate immune system and is held in ‘check’ primarily by eosinophils and macrophages.

leukocytes:

white blood cells, the primary cells of the innate and the adaptive immune systems that work against infection and tissue damage.

eosinophils:

a type of leukocyte whose major function is to dampen inflammatory responses and to ingest and kill microorganisms.

monocyte:

a type of leukocyte that is transported by the blood into tissues where it transforms into a macrophage through the process known as monocyte-macrophage differentiation.

macrophage:

a monocyte that has settled and matured in tissue where it defends against microorganisms and removes dead tissue and ‘debris’ by ingesting them. Macrophages also control the progression and time duration of the inflammatory response to keep this immune response from spilling over into a pathological inflammation with increasing heat and fluid swelling. They are responsible for the recruitment of lymphocytes from the adaptive immune system to provide more effective protection against infection.

neutrophil:

a type of leukocyte whose primary function is ingesting and killing bacterial microorganisms as well as playing an important role in the defense against viral infections.

lymphocyte:

a type of leukocyte found in the lymph nodes, spleen, and other lymphoid organs that has ‘memory’ for specific recognition of antigens; its primary role is fighting chronic bacterial and acute viral infections and it has the capacity to destroy and remove antigen particles quickly and robustly.

 

2006 © Copyright Joseph Thomas, PhD

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Footnotes / References:

• The Easy Keeper: Myth and Dangers. Joseph Thomas, PhD, Natural Horse (2006) Vol 8 Issue 4.
• Principles of Internal Medicine, Vol II, 16th edition, D.L. Kasper, MD, et.al. 2005, McGraw-Hill.
• The Relationship Between Natural Hoof Wall Growth and Laminitis. Joseph Thomas, PhD, Natural Horse (2005) Vol 7 Issue 5.
• The Missing Link in Laminitis. Joseph Thomas, PhD, Natural Horse (2006) Vol 8 Issue 4.
• 1 beta- Hydroxysteroid Dehydrogenase Type1 is Induced in Human Monocytes Upon Differentiation to Macrophages. R. Thieringer, et.al. The Journal of Immunology, 2001, 167: 30-35.
• The Expression of 11beta-Hydroxysteroid Dehydrogenase Type1 by Lymphocytes Provides a Novel Means for Intracrine Regulation of Glucocorticoid Activities. T.Y.Zhang, et.al., The Journal of Immunology, 2005,, 174: 879-889.
• S. Piscopo, DVM, PhD. American Journal of Veterinary Research, 2003, 64 (3), 279-283.

 

Acknowledgements: I would like the reader to be aware that this article would not have been possible if not for the editorial skill and countless discussions with my wife Crystal Leaman, general manager of For Love of the Horse.

About the author:

Joseph Thomas, PhD, has been a practitioner, teacher and consultant in Chinese medicine for more than twenty years. Prior to his commitment to Chinese medicine Dr. Thomas was a researcher at the Massachusetts Institute of Technology engaged in medical research. He joined these skills together with his love of horses and developed For Love of the Horse, LLC along with his wife and daughter.